SAFETY AND FEASIBILITY OF MAGNETIC RESONANCE-GUIDED HIGH INTENSITY FOCUSED ULTRASOUND
(MR-HIFU) FOR THE ABLATION OF RELAPSED OR REFRACTORY PEDIATRIC SOLID TUMORS INCLUDING
DESMOID TUMORS
AeRang Kim, MD, PhD1; Karun V. Sharma2; Pavel Yarmolenko3; James I. Geller4; Joseph G. Pressey4; John M. Racadio5; Haydar Celik3; Avinash Eranki3; Matthew Lanier6; Caitlin Tydings1; Ari Partanen7; Peter C. Kim8
1Oncology, Childrens National Medical Center, Washington, USA; 2Interventional Radiology, Children’s National Medical Center, Washington, , USA; 3The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Medical Center, Washington, USA; 4Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;
5Interventional Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 6Imaging Research Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 7Profound Medical Inc., Mississauga, ON, Canada; 8Surgery, George Washington School of Medicine, Washington, USA
Objective: Acute and late effects of current multi-modal therapy in pediatric cancer are substantial, and the prognosis for recurrent/refractory sarcomas and solid tumors remains dismal. Magnetic resonance guided high intensity focused ultrasound (MR-HIFU) is an ultrasound-based technology that can raise tissue temperature with millimeter spatial accuracy under MR thermometry guidance. Advantages over conventional local tumor control such as surgery or radiation therapy are that MR-HIFU is non-invasive, non-ionizing, and enables ablation of large tumor volumes under real-time image guidance. MR-HIFU has been studied in a variety of solid tumors in adults and for the relief of pain from bone metastases. There is evidence that MR-HIFU may improve systemic disease control by stimulating an anti-tumor immune response. The primary objective of this clinical trial is to determine the safety and feasibility of MR-HIFU ablation in children, adolescents, and young adults with relapsed/refractory solid tumors. Secondary objectives include the evaluation of changes in functional imaging, quality of life, and immune markers in children treated with MR-HIFU.
Methods: In this multi-institutional trial (NCT02076906), patients ≤ 30 years of age with relapsed/refractory solid tumors including desmoid tumors are eligible. Tumor target lesions are limited to those located in or close to bone at sites accessible to MR-HIFU. Patients with target lesions in the skull or spine or patients with any contraindication for MRI are excluded. Patient imaging and eligibility are reviewed by our multi-disciplinary HIFU team. Patients undergo MR-HIFU treatment of the selected lesion(s) under general anesthesia. Tolerability is defined during the 14 days following MR-HIFU ablation. Disease status is evaluated using standard imaging techniques post-treatment. Quality of life assessments using patient reported outcomes and immune pharmacodynamic markers are collected at baseline and during interval follow-ups post-treatment.
Results: Eleven evaluable patients [6M, 5F; median age 14 years (range 4-21)] with osteosarcoma (n=1), Ewing sarcoma (n=1), rhabdomyosarcoma (n=1), and desmoid tumor (n=8) have enrolled to date at two treatment centers. A total of 17 HIFU treatments were administered (2 patients underwent ablation of another target lesion, 2 patients underwent ablation of the same incompletely treated target lesion, one patient underwent ablation of the same target lesion 3 times). Only two HIFU treatments were technically unsuccessful due to the inability to achieve ablative temperature at the target location. There was no treatment limiting toxicities. One patient had a grade 3 skin burn requiring debridement. All other related toxicities were mild (grade 1/2) and reversible including transient pain (n=4), first or second degree skin burn (n=3); and transient paresthesia, neuropathy, skin discoloration, and gait disturbance due to pain (n=1 each). One target lesion was completely ablated; however, the patient progressed at other sites of disease. All other target lesions were partially ablated, either due to technical limitations or nearby critical structures.
Conclusion: MR-HIFU ablation of solid tumors in children, adolescents, and young adults appears to be safe and feasible. Changes in quality of life patient reported outcomes and immune markers’ analyses are underway. Tumor volumetric analysis of perfusion for disease response post ablation therapy is being evaluated.

 

Poster #335 3214469
SANDWICH ISOLATION SURGERY PREVENTS LOCAL RECURRENCE IN PROGRESSIVE DESMOID TUMORS: A PILOT OBSERVATIONAL STUDY
Junqiang Yin; Yiwei Fu; Changye Zou; Gang Huang; Jingnan Shen
The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
Objective: Desmoid tumors are highly recurrent especially when involving nerves and blood vessels. Isolating desmoid tumors from normal tissues with artificial barriers may deprive desmoid tumors of nutrients. The aim of this observational study was to prospectively assess the efficacy of a new surgery technique, named as sandwich isolation surgery, on preventing the local recurrence of progressive desmoid tumors.
Methods: Patients with progressive desmoid tumor involving adjacent nerves and blood vessels and received sandwich isolation surgery were eligible for enrolment. Sandwich isolation surgery refers to using a biomaterial un-absorbable patch to envelop involved neurovascular bundles after marginal or intralesional excision of desmoid tumors, isolating residual tumor or tumor bed from normal tissue, and forming a “normal tissue- biomaterial patch -tumor/tumor bed- neurovascular sheath” sandwich structure.
Results: Nine patients were included in the study. Among them, six had recurrent tumors and received at least once resection surgery before sandwich isolation surgery. These patients were followed up for 16.7-56.7 months (median: 31.6 months). After the sandwich isolation surgeries, no local recurrence was observed in eight of them. As for the rest one with local recurrence 11.5 month after excision, magnetic resonance images demonstrated that recurrent tumor was located only in the region where neurovascular bundles were not isolated. No adverse event associated with the enclosed neurovascular bundles was observed in all patients.
Conclusion: Sandwich isolation surgery was a new and low-cost technique to prevent the local recurrence of desmoid tumors, even if residual tumors remain around neurovascular bundles, which avoided functional impairment caused by repeated operations.

 

Poster #010 3250654
DESMOID TUMOR VOLUMETRIC ANALYSIS FOR DISEASE RESPONSE POST ABLATION WITH MAGNETIC RESONANCE GUIDED HIGH INTENSITY FOCUSED ULTRASOUND (MR-HIFU)
Caitlin Tydings1; Pavel Yarmolenko1; James I. Geller2; Joseph G. Pressey2; John M. Racadio2; Haydar Celik1;
Avinash Eranki1; Matthew Lanier2; Karun V. Sharma1; AeRang Kim1
1Children’s National Medical Center, Washington, USA;
2Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Objective: An objective measure of treatment response is an important feature of the clinical evaluation of cancer therapy. Response Evaluation Criteria in Solid Tumors (RECIST) is a unidimensional measurement that is currently the most widely accepted method of measuring treatment response. This may be suitable for more uniform, rapidly growing, malignant solid tumors; however, its limitations are most notable in irregularly shaped, heterogeneous tumors, particularly when treated using targeted or local therapies.
Desmoid tumors are benign, locally aggressive and irregularly shaped tumors that can cause significant deformity, morbidity and mortality resulting from local mass effects causing compression and pain, muscular contracture or obstruction of adjacent neurovascular structures. MR-HIFU ablation can be used to target specific areas within larger tumors that may be contributing most to this type of morbidity. The resultant ablation zone can be visualized as a volume of non-perfused and non-enhancing tissue on contrast enhanced MRI imaging. Measuring total tumor, perfused and non-perfused volumes using volumetric analysis may provide better objective measurements of tumor response to MR-HIFU local therapy compared to unidimensional measurements.
Methods: This is a retrospective review of MRI images from 9 patients with histologically diagnosed recurrent, refractory and symptomatic desmoid tumors from Children’s National Medical Center (CNMC) and Cincinnati Children’s Hospital Medical Center (CCHMC). All patients were treated with MR-HIFU on a clinical trial or compassionate use protocol. Unidimensional measurements were performed using digital calipers on Synapse workstation and Osirix workstation for patients from CNMC and CCHMC, respectively. Volumetric analysis was performed using Osirix software. Total tumor volume (TTV) was segmented and calculated by outlining the tumor in all axial planes on post-contrast T1-weighted images. Non-perfused volume (NPV) was similarly measured on axial planes using subtraction images that were generated from pre- and post-contrast T1-weighted images. Perfused tumor volume (PTV) was measured as the subtraction of NPV from TTV.
Results: Nine patients (median age 15.3 years, range 6-23 years; 4 males) underwent treatment (tx) with MR-HIFU (n=3, 1 tx; n=5, 2 tx; n=1, 3 tx). Tumors were axial (n=3) or located in the lower extremities (n=6). The median pretreatment TTV was 266.9 cm3 (range 19.7 – 657.2 cm3). NPV was not measurable pre-treatment and TTV equaled PTV. At one month post-treatment, the median TTV was 278.2 cm3 (range 23 – 675.7 cm3), median PTV was 214.3 cm3 and median NPV was 64 cm3. There were no objective RECIST responses immediately post treatment. Table 1 shows individual volumes for all patients. Figure 1 demonstrates volumetric analysis for patient 1 including outlined TTV (white) and NPV (red).
Conclusion: Volumetric analysis provides more detailed measurements of treatment effect including percentages of perfused and non-perfused tumor volume that is not reflected by unidimensional measurements, which may better determine treatment effects with HIFU therapy. Small increases in TTV are thought to be due to inflammation and edema post ablation treatment. These volumes are useful measurements that can be followed over time to establish how changes in TTV relate to perfused and non-perfused tumor components. Analysis of subsequent imaging at later follow up periods, as well as following retreatment, is ongoing and will be included at time of presentation.

 

Poster #013 3254342
TWO WEEKS INTERVAL OF METHOTREXATE AND VINBLASTION CHEMOTHERAPY SHOWS THE SIMILAR EFFECT AS WEEKLY ADMINISTRATION
Yoshihiro Nishida, MD, PhD1; Tomohisa Sakai2; Hiroshi Koike2; Hiroshi Urakawa2; Eisuke Arai2;
Kunihiro Ikuta2; Yuichi Ando3; Koki Shimizu4; Naoki Ishiguro2
1Rehabilitation, Orthopaedic surgery, Nagoya University Hospital, Nagoya, Aichi, Japan; 2Orthopaedic Surgery,
Nagoya University Graduate School and School of Medicine, Nagoya, Aichi, Japan; 3Medical Oncology, Nagoya
University Graduate School and School of Medicine, Nagoya, Japan; 4Orthopaedic Surgery, Tonokosei Hospital,
Mizunami, Japan
Objective: Several studies have shown efficacy of low-dose chemotherapy with methotrexate (MTX) and vinblastine (VBL) for desmoid-type fibromatosis (DF). Many regimens in these studies used a weekly dosing regimen to demonstrate their effectiveness. Since 2003, meloxicam, which is a selective COX-2 inhibitor, has been administered consecutively and prospectively, as a first line treatment. We have used MTX + VBL chemotherapy in a regimen of once every two weeks, which was different from that used in previous reports, for refractory patients. The aim of this study was to reveal the clinical outcome of low-dose chemotherapy with MTX+VBL in a regimen of once every two weeks, additionally to determine the useful factors to predict the efficacy of this chemotherapy including CTNNB1 mutation status.
Methods: Since 2003, 167 cases were histologically diagnosed as DF. Among them, 36 cases were treated with MTX (30mg/M2) +VBL (6mg/M2) chemotherapy. Treatment interval was basically 2 weeks according to our previous study. However, the dosing interval was extended to once every 3-4 weeks depending on the patient’s side effects and preference, and tumor reduction effects. Effectiveness was evaluated with MRI and/or CT every 3 months according to Response Evaluation Criteria in Solid Tumors (RECIST). Frozen or FFPE (Formalin-Fixed Paraffin-Embedded) specimens obtained at biopsy or previous surgery were subjected to the analyses for CTNNB1 mutation status by Sanger method. Clinical outcome with this 2-weeks interval regimen was investigated, and factors correlating with the efficacy were analyzed.
Results: Male was 13, female was 23 cases, mean age at the treatment was 36±18 years. Mean maximum diameter of tumor was 15±18 cm. Twenty-nine cases (81%) had CTNNB1 or APC mutation. Mean treatment duration and cycles of MTX+VBL were 20 months and 29 cycles, respectively. According to RECIST, PD in 2, PR 1n 15, and SD in 19. Response rate (PR) was 42%, and clinical benefit rate (PR+SD) was 94%. It took an average of 10 months to show a response in PR cases. According to CTCAE, Grade 3 or more adverse events were observed in only one case (2.8%) As factors relating to the response rate, CTNNB1 mutation status, gender, age, size, and location did not affect the outcome with RECIST evaluation. Longer treatment duration and cycles of chemotherapy were significantly associated with the outcome (P=0.003 and 0.005, respectively). In 15 cases of PR, recurrent tumors significantly took longer time to get efficacy (P=0.027), and tumors arising in trunk and extremities tended to take longer time (P=0.1).
Conclusion: Every 2-weeks’ regimen showed 42% of response rate, which was similar to those (40-52%) reported in previous studies (every week regimen). Rate of grade 3-4 toxicity was 2.8% in our study, which was lower than those (13-40%) reported in previous studies (every week’s regimen). On the other hand, time to response in the present study was 10 months (mean), which was longer than that (6 months, mean) reported with every week’s regimen.
Low-dose MTX+VBL chemotherapy with 2-weeks’ regimen is effective treatment for refractory DF regardless of various clinical factors and CTNNB1 mutation status. It will take time to obtain objective response.

 

Poster #018 3255781
DEVELOPMENT OF MULTIFOCAL EXTRA-ABDOMINAL DESMOID FIBROMATOSIS AFTER SURGICAL RESECTION
Brendon Bauer; Nadine L. Williams; Stephen Morris; Alex Mierke; Omar Ramos; Lee M. Zuckerman
Orthopaedic Surgery, Loma Linda University Medical Center, Loma Linda, CA, USA
Objective: Multifocal extra-abdominal desmoid fibromatosis is a rare entity. Both sporadic and hereditary entities have been described. Trauma has been described as a possible etiology of sporadic fibromatosis. We report on two cases of solitary, sporadic fibromatosis that developed multifocal disease after surgery.
Methods: The cases of a 21-year-old female with fibromatosis involving the right hemipelvis (Figure 1) and a 20-year-old male with involvement of the right ankle (Figure 2a) were reviewed. Both patients had a negative evaluation for Gardner syndrome including a colonoscopy. Biopsy was performed on two separate tumors that developed after surgery to confirm multifocal disease.
Results: Both patients developed distant multifocal disease in the extremity affected by the surgery. Neither patient had multifocal disease prior to their last surgery. The 21-year-old female underwent a single surgery with resection of the primary tumor including ligation and en bloc resection of the femoral vein and lymphatics. She developed significant lymphedema post-operatively. Five years after surgery she was found to have multiple tumors in her right leg below the knee (Figure 3). The 20-year-old male presented after multiple resections at an outside institution with local recurrence and fungation of the tumor. Multiple procedures were performed in order to attempt limb-salvage surgery. The patient elected to proceed with a below the knee amputation after multiple recurrences. Post-operatively the patient developed sores and folliculitis multiple times under his prosthesis due to sweating while working. Thirty-two months after amputation, the patient developed tumors at the posterior aspect of his stump and the popliteal fossa where his prosthesis was irritating the soft tissues (Figure 2b). Both patients elected for non-surgical management and the tumors are stable 2.5 and 3 years after the diagnosis of multifocal disease. No evidence of disease outside of the affected extremity has developed.
Conclusion: Multifocal fibromatosis is rare. These two cases are felt to have developed after chronic irritation and trauma to the soft tissues due to significant lymphedema and from use of a prosthesis. Chronic inflammation and repetitive trauma may be considered a risk factor for developing multifocal disease.

 

Poster #021 3256403
COMBINATION DRUG THERAPY AND AGGRESSIVE FIBROMATOSIS
Puviindran Nadesan, BSc1; Raymond Poon2; Vijitha Puviindran1; Mushriq Al-Jazrawe4; Sean Ryan1; Alessandro Datti6; Robert Maki5; Alexander Lazar3; Benjamin Alman1
1Orthopaedic Surgery, Duke University, Durham, NC, USA; 2Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; 3MD Anderson, Houston, TX, USA; 4Broad Institute, Cambridge, ME, USA; 5Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA; 6Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada
Objective: Aggressive fibromatosis (AF), commonly referred to as Desmoid tumor, is a locally aggressive lesion. Surgery is associated with a high recurrence rate, and in recent years there has been increased interest in non-surgical management. Clinical studies are limited by small patient numbers and the need for long term follow up. As such, preclinical studies to assess possible therapies are useful in informing treatment approaches. Prior studies investigated single agent therapies through both in vivo and in vitro studies; however, there is a paucity of literature available on multi-drug regimens. A multicenter drug screen has identified numerous medications that show promising activity in AF. Therefore, we sought to investigate various combination regimens from the drug screen to determine drug synergies and the utility of multidrug therapy in AF.
Methods: Our mouse model, APC1638N, develops AF tumor that is structurally similar to human AF tumor. In this study, we chose male mice that develop around 25 tumors per mouse by the age of 6 months. The treatment was started when the mice are around 8 weeks old (2 months) and continued until sacrificed at the age of 6 months. At which, an observer who is blinded to the groups, manually counted the tumors and measured tumor volume. Mice were treated with either monotherapy or combination therapy. Drugs which were effective as single agents in initial analyses were studied in combinations. Dexamethasone (Dex), Dasatinib (Das), AV-412 tosylate (AV), FAK inhibitor 14 (FAK), IKK-16 (IKK), PF-03084014 (PF), KB-R7943 mesylate (KB), Nefopam (Nef), and Y26763 (Y267) were selected for therapy. AF tumors were also evaluated through immunohistochemistry (IHC) for markers of proliferation and apoptosis (KI67 and caspase).
Results: Gross tumor analysis from Apc+/Apc1638N mice has shown a significant decrease in tumor number with most combinations. We found that the following combinations significantly reduced tumor number or the volume in the APC1638N mice without adversely affecting the mouse: Dex + FAK, Dex + Das, Dex X Y267, Dex X AV, Dex X IKK, Das X FAK, Das X AV, Das X Y267, Das X PF, Das X KB, AV X FAK, AV X PF, AV X KB, AV X IKK, FAK X Y267, FAK X KB, FAK X IKK, IKK X PF, IKK + KB, PF + KB, KB + Nef, Y267 + Nef. IHC demonstrated increased caspase activity and decreased KI67 activity for the combination chemotherapy treatments.
Conclusion: Desmoid tumors are locally aggressive lesions and due to high local recurrence rates, there is a need for effective chemotherapeutic options. Based on the preliminary results of this study, combination therapy appears to be effective treatment options, which may warrant further evaluation with clinical trials.

 

Poster #022 3256572
CRYOABLATION FOR DESMOID TUMORS: THE FRENCH NATIONWIDE CRYODESMO-01, CURRENT PRACTICE AND PERSPECTIVES
Jen Wmmanuel Kurtz, MD, PhD9; Xavier Buy1; Erik Sauleau8; Maud Toulmonde2; Frédéric Deschamps3; Charles Honoré4; Amine Bouhamama5; Jean-Yves Blay6; Afshin Gangi7
1Interventional Radiology, Institut Bergonié, Bordeaux, France; 2Medical Oncology, Institut Bergonié, Bordeaux, France; 3Interventional Radiology, Institut Gustave Roussy, Villejuif, France; 4Surgery, Institut Gustave Roussy, Villejuif, France; 5Interventional radiology, Centre Léon Bérard, Lyon, France; 6Medical Oncology, Centre Léon Bérard, Lyon, France;
7Interventional radiology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 8Statistics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 9Medical Oncology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Objective: Desmoid tumors (DT) are rare tumors (2-4 cases/million/year) that originate from musculoaponeurotic structures, and related so APC or beta-catenin gene alterations. Cryoablation is a promising interventional radiology technique that is suitable for DTpts. The procedure is based on repeated cycles of freezing/passive thawing of the tumor, leading to cell death. CRYODESMO-01 was a nationwide phase II study assessing cryoablation in advanced DT. Retrospective data for cryoablation in expert centers with long-term follow up are also available in patients treated before CRYODESMO, and provide useful data for further developement of the technique.
Methods: CRYODESMO-01 was the first prospective, open-label, non-randomized, non- comparative, multicentric pilot study assessing cryoablation in non-abdominopelvic DT pts progressing after two lines of treatment. The study was funded by the French National Cancer Institute and supported by the French Sarcoma Group and the SOS Desmoid pts advocacy group.The primary endpoint was the rate of non-progression at 12 months; secondary endpoints included safety, time to disease progression (TDP), quality of life (QoL), assessment of pain and functional status. Inclusion criteria were: pts 18 y.o., confirmed DT deemed accessible by the cryoablation operator , progressive disease after at least two lines of adequate medical therapy or with functional symptoms/pain, adequate biological parameters, informed consent and affiliation to social security. Data from CRYODESMO will be compared to a series of patients treated in an expert center to provide longer follow-uo experience and additional data, to support further development of cryoblation.
Results: 50 pts were enrolled from in 4 centers (78% female). The mean age was 41 y.o (range 19-73). Tumor location included limbs (36%); trunk (60%) and cervical area (4%). The median tumor volume was 111cm3(range 0.6-1 068). The rate of non-progressing disease +12 months was 86% (CI95% 73%-94%). Grade 1 and 2 toxicity occured in 32.8 and 44.5% of cases, whereas 11 pts (22%) had grade 3 and 4 AEs, all with a favorable outcome. Overall, 63% and 83% of pts experienced an improvement in functional status (better utility) and pain scores, respectively. Data from our expert center reinforce the feasibility of cryoablation in large tumors, as well as DT of the extermities, showing functional benefit and strong reduction of analgesics intake, suggesting that a cure might be achievable with this innovative technique.
Conclusion: Cryoablation is feasible in progressive DT pts, and has a favorable safety profile. The primary endpoint of the study was met and coupled with expert centers retrospective experiencen support the future incorporation of cryoablation. Cryoablation will soon challenge medical therapy as front-line therapy in the forthcoming randomized trial (CRYODESMO-02).

 

Poster #023 3257659
CAN WAIT AND SEE BE THE STANDARD OF CARE FOR INITIAL APPROACH TO PRIMARY SPORADIC DESMOID TUMORS? PRELIMINARY DATA FROM MULTICENTER EUROPEAN PROSPECTIVE STUDIES
Chiara Colombo1; Milea Timbergen4; Paola Boccone2; Dirk Grunhagen4; Erica Palesandro2; Marco Fiore1; Alba Bianco1; Federica Perrone1; Elena Palassini1; Lorenzo D’Ambrosio2; Silvia Stacchiotti1; Paola Collini1; Angelo Paolo Dei Tos3;
Paolo Casali1; Giovanni Grignani2; Alessandro Gronchi1; Cornelis Verhoef4
1Fondazione IRCCS Istituto Tumori Milano, Milan, Italy; 2IRCCS Istituto Candiolo, Candiolo, Italy; 3Ospedale di Treviso, Treviso, Italy; 4Erasmus MC Cancer Institute, Rotterdam, Netherlands
Objective: In recent years, retrospective evidence of long term disease stabilization and spontaneous regression of sporadic desmoid tumor (SDT) has been provided. As a result, a frontline wait and see approach (W&S) has been more routinely proposed. CTNNB1 coding for β-catenin is mutated in more than 90% of patients. Furthermore, a specific mutation (45F) was found to be correlated with a worse post-surgical outcome. However, the prognostic role of β-catenin mutations is not fully understood and has never been explored in patients under W&S before any active therapy is performed. The main objective of this study was to prospectively evaluate the role of W&S in patients with primary SDT and to correlate β-catenin mutational status with the clinical outcome.
Methods: This study comes from the combination of 2 prospective European multicenter (Italian and Deutch centers) observational studies aimed at evaluating the progression rate in patients affected by primary SDT managed with a front-line conservative approach (W&S). β- catenin mutational status was analyzed.
Inclusion criteria were:
-Pathological diagnosis of SDT
-Primary disease at diagnosis or incompletely resected residual disease (R2 resection)
-Histological diagnosis confirmed by expert sarcoma pathologists according to the WHO criteria
-Measurable disease evaluated by on contrast-enhanced MRI (ce-MRI) T1 and T2 weighted images or contrast enhanced CT scan (for intra-abdominal location) or ultrasound
Patient and tumor-related factors, treatment variables, follow up findings, time to progression and status at last follow-up were recorded. Follow-up (FU) schedules were identical in the 2 studies and required clinical evaluation and ce-MRI (or CT scan or ultrasound) at 3, 6, 9, 12 months, then every 6 months until the third year. Upon progression (RECIST or not), defined as tumor growth proven by imaging and/or clinical examination, active treatments were proposed according to physician’s preference and registered in the clinical database.
Results: Between 2013 and 2018 a total of 199 patients with CTNNB1 mutational status available (except one for which the analysis is pending) entered the study (81% female, 19% male); median age 39 (IQ, 33-48) years; sites distribution: abdominal wall (46%), trunk (27%), extremity (18%), intra-abdominal (3%), head/neck (6%). Median follow-up was 18 (IQ, 10-28) months. At the time of last follow up: 11/199 had spontaneous complete regression, 41/199 spontaneous partial regression, 86/199 stable disease, 61/199 progression. 31/71 patients started an active treatment for PD. The median time to an active treatment was 8 (IQ range, 5-13) months. A preliminary analysis on the correlation between β-catenin mutational status and outcome revealed that 9/26, 8/108, 2/25 and 4/39 patients with DT harboring 45F, 41A, WT or other mutations had to start an active treatment for progression, respectively. Ten patients required surgery after enrollment.
Conclusion: This study prospectively confirmed that W&S for primary SDT is safe in light of the high rate of regressions and spontaneous growth arrest. SDT have a favorable course in more than 60% of patients. A higher risk of worse outcome for patients harboring 45F was observed on the initial analysis but needs further validation on a longer FU. Upon progression, active treatments were considered on an individualized basis, while persisting in the W&S could still pay off.

 

Poster #108 3241854
DIMENSIONAL AND NON-DIMENSIONAL CHANGES WITH LOW-DOSE CHEMOTHERAPY IN SPORADIC DESMOID TUMORS (DT)
Edoardo Zanchetta1; Chiara M. Ciniselli2; Chiara Colombo3; Silvia Stacchiotti4; Giacomo Baldi4; Salvatore Provenzano4; Rossella Bertulli4; Noemi Simeone6; Alessandra Casale5; Francesca G. Greco5; Paolo Verderio2; Marco Fiore3;
Alessandro Gronchi3; Paolo Casali4; Carlo Morosi5; Elena Palassini4
1Postgraduation School in Radiodiagnostics, Università degli Studi di Milano, Milan, Italy; 2Unit of Bioinformatics and Biostatistics – Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 3Oncological Surgery Unit 4, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 4Medical Oncology Unit 2, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 5Diagnostic and Interventional Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 6Postgraduation School in Medical Oncology, Università degli Studi di Milano, Milan, Italy
Objective: A number of medical therapies were shown to be active in DT, including low-dose methotrexate (MTX) plus vinca alkaloids. Considering that RECIST criteria may underestimate chemotherapy activity, we herein report on the results of a retrospective study investigating changes in volume and MRI T2-weighted signal intensity in sporadic DT treated with low-dose MTX plus vinca alkaloids.
Methods: We retrospectively reviewed all cases of sporadic DT treated with low-dose weekly MTX plus vinca alkaloids at our institution over the last 20 years, evaluated by Magnetic Resonance Imaging (MRI). Chemotherapy was administered weekly until reaching a number of cycles between 40 and 50 or until reaching one year of treatment. MRI at baseline, at 6 and 12 months from start of chemotherapy, at the end of treatment and during follow-up were analyzed. A manual segmentation of the lesions in a slice-by-slice fashion was performed using IntelliSpace Portal Tumor Tracking software (Philips); diameters, volume and mean T2 signal intensity of the lesions (which was then normalized to the intensity of the muscle) were obtained. Descriptive statistics and graphical representation were implemented.
Results: We identified 27 sporadic DT patients eligible for the study. There were 23 females (85%) and 4 males (15%). The median age was 39,8 years (range 18,1-68,4 years). Tumor site was: extremities/girdles, abdominal wall, thoracic wall, neck and intra-abdominal in 11 (41%), 7 (26%), 4 (15%), 3 (11%) and 2 (7%) patients, respectively. All patients were progressing before starting chemotherapy. The median duration of chemotherapy was 13,9 months (range 3,5-18,5 months) for a median number of cycles of 40 (range 12-63). Reasons for chemotherapy discontinuation were treatment completion in 26 patients (96%) and progressive disease according to RECIST in 1 case (4%). According to RECIST criteria, best response was: partial response (PR) in 7 patients (26%), stable disease (SD) in 18 (67%; with a minor dimensional reduction in 17 and a minor increase in 1) and progressive disease (PD) in 2 (7%). When considering tumor volume, a reduction of at least 65% (roughly equivalent to 30% decrease in one diameter as per RECIST) was achieved in 11 subjects (41%), a smaller volume decrease in 13 (48%) and a tumor volume increase in 3 (11%). Six patients (22%) had a minor decrease or even a slight increase in longest diameter while showing a tumor volume reduction greater than 65% (apparently, lesions shrank without diminishing in the main diameter). When considering normalized T2 signal intensity, a decrease of at least 50%, as best response, was observed in 14 patients (52%), a minor reduction in 9 patients (33%) and an increase in 4 patients (15%). By looking at the three parameters altogether, Figure 1 reports best responses achieved with chemotherapy for each patient. In 3 cases an important discrepancy between dimensional (mono-dimensional and volumetric) changes and T2 signal intensity changes was observed. In particular, in 2 patients T2 signal intensity increased despite a decrease in volume: in one case, clinical worsening was observed during treatment and several further treatments were administered after chemotherapy interruption; the other patient was asymptomatic and stopped treatment just one year ago. In one additional case, volume increased significantly during the first months of treatment, than a reduction was observed, while T2 signal intensity decreased; the patient stopped treatment 3 years ago and is asymptomatic.
Conclusion: In this series of DT treated with low-dose chemotherapy, dimensional reductions were observed in the vast majority of patients, even if RECIST partial responses were achieved in a relatively small number. Normalized T2 signal intensity changes may be more informative, especially when diverging from dimensional variations. An effort to better understand correlations between dimensional changes, T2 signal intensity changes and clinical outcome is ongoing.

 

Poster #133 3252978
CTNNB1 MUTATIONS AND AGGRESSIVE BEHAVIOR IN NEUROMUSCULAR CHORISTOMA-ASSOCIATED FIBROMATOSIS
Jodi M. Carter, MD, PhD; Andres Maldonado; Matthew Howe; Robert J. Spinner
Mayo Clinic, Rochester, MN, USA
Objective: Neuromuscular choristoma (NMC) is a rare, developmental malformation that typically arises in the major proximal peripheral nerves, most commonly the sciatic nerve. NMC is strongly associated with development of a peri-lesional desmoid-type fibromatosis (DTF). Previously, we reported that activating CTNNB1 mutations occur in NMC and NMC-fibromatosis, similar to those seen in sporadic DTF. As CTNNB1 mutational subtypes have established prognostic and predictive significance in sporadic DTF, we evaluated the frequency of CTNNB1 mutational subtypes and the clinical outcomes in a series of patients with NMC-fibromatosis.
Methods: With institutional approval, cases coded as neuromuscular choristoma and desmoid-type fibromatosis, with available formalin-fixed, paraffin-embedded (FFPE) tissue were retrieved. Clinical data, radiologic images and pathologic material were reviewed. Archival FFPE tissues, enriched for NMC-fibromatosis, were macro-dissected. Genomic DNA was extracted using the QIAamp® DNA FFPE Tissue kit (QIAGEN, Valencia, CA) and amplified by polymerase chain reaction using primers specific for the region surrounding CTNNB1 codons 41 and 45, followed by pyrosequencing and mutation analysis.
Results: Seven cases of biopsy-proven NMC-fibromatosis, occurred in 3 females and 4 males (median age at diagnosis: 14 y, range 5 to 51y) with biopsy-proven (N=5) or radiologic diagnosis (N=2) of NMC of the sciatic nerve. In all cases, NMC-fibromatosis arose within the affected nerve territory: involving the soft tissues of the buttock, posterior thigh or popliteal fossa, and cases developed following NMC biopsy (N=5) or spontaneously (N=2). All 7 NMC-fibromatosis contained CTNNB1 mutations, including 5 p.S45F, 1 p.S45P and 1 p. T41A. In 6 cases with clinical follow-up (mean 3.5 y; range 1-8y), all patients had disease progression, irrespective of initial treatment modality: surgical resection (N=3) cryoablation (N=1), tamoxifen (N=1) or observation (N=1). One patient developed multifocal, metachronous NMC-fibromatosis at spatially-distinct sites along the NMC-affected nerve. Disease stabilization was achieved with adjuvant radiation therapy (N=3), doxorubicin-based chemotherapy (N=1) or receptor tyrosine kinase inhibitor-based therapy (e.g. sorafenib) (N=1).
Conclusion: NMC-fibromatosis frequently harbors CTNNB1 p.S45X mutations and displays aggressive biologic behavior, requiring adjuvant local or systemic therapy for disease stabilization. As such, and as development of NMC-fibromatosis is frequently precipitated by iatrogenic injury (i.e. biopsy) of the NMC, we now employ a “no-touch” approach for the diagnosis of NMC, and rely on clinical and MR imaging features for both diagnosis and surveillance whenever possible.

 

Poster #151 3219544
IN SITU CRYO-ABLATION OF DESMOID TUMORS ASSISTED BY 3D MODELLING AND NAVIGATION BY O ARM
Ortal Segal; Ido Druckmann; Yehuda Kollander; Solomon Dadia; Amir Sternheim; Yair Gortzak
The National Unit for Orthopedic Oncology, Tel Aviv Medical Center, Tel Aviv, Israel
Objective: Aggressive fibromatosis, is a rare, locally invasive, non-metastasizing condition. The natural history of desmoid tumors is variable and includes periods of indolence, growth, and regression.
Reasons for treatment and how? Volumetric progression, Symptoms worsening & Cosmetic disturbance.
Large en-bloc surgery is no longer regarded as the cornerstone treatment. Rate of relapse after surgery exceeds 60% in larger series. Shift to a more conservative approach, the ‘wait-and-see’ policy was adopted during last years.
Other forms of treatment include: radiation, systemic therapy, and neoadjuvant radiation with or without chemotherapy. neither approach has emerged as optimal or definitive, and each is associated with high recurrence rates or complications from the treatment itself.
In situ cryotherapy is a minimal invasive procedure that can decrease tumor size by apoptosis. cryotherapy is a safe procedure the does not damage collagenous structures surrounding the tumor. During the procedure, the ice ball in the tumor can be monitored using imaging studies such as CT or ultrasonography. The proper position and the number of needles is crucial in order to ideally cover and surround the tumor mass. By 3D modelling and planning this goal can be achieved. The most effective trajectory can be determined and vital organs (nerves, blood vessels and other structures) can be protected. Using the O arm navigated system, real time positioning and monitoring is possible.
Methods: 11 patients with histolocally confirmed extra abdominal desmoid tumor with progression of tumor mass on imaging and severe functional disturbance were treated with in situ cryosurgery. All patients were scanned by MRI and CT prior the procedure. Segmentation of the tumor and surrounding structures was perform into 3D surface models. Then by extrapolating the “kill zone” of each cryotherapy needle we placed the needle in to the tumor. All procedures took place at the operating theater under general anesthesia. According to previous planning, several isolated cryo needles (Galil medical ice-rod plus, Israel) were inserted into the tumor mass under O arm navigated guidance. Then cryotherapy protocol was activated which includes 10 minutes freezing, 5 minutes active thawing and repeated 10 minutes freezing. During freezing cycles, a scan by the O arm was done in order to monitor the “ice ball” in the tumor.
Results: 10 tumors progression has stopped. 2 patients underwent repeated ablation do to relative tumor growth. in 6 patients (54.5%) – there was average of 53% reduction in tumor volume within 6 months. In 2 patients the tumor disappeared completely. In 3 patients the tumor as stopped growing but no reduction was noted. One patient the tumor is growing (close to brachial plexus) and One patient data collection is missing (Russia). Quality of life – SF 36 – physical health, emotional health and pain was significantly improved.
Conclusion: In situ cryo-surgery in a safe procedure and effective in stabilizing tumor mass in desmoid tumors. In 90% of the patients we were able to stop tumor growth and improve quality of life. By 3D modelling correct positioning of cryo needles can be optimal and safer for the patients.

 

Poster #183 3223161
THERAPEUTIC VALUES OF RADIOTHERAPY IN THE TREATMENT OF DESMOID TUMORS
Yoo-Kang Kwak, MD, PhD1; Chul Seung Kay1; Yeon Sil Kim2; So Jung Lee1; Ji Hyun Hong1; Eun Young Park2
1Radiation Oncology, Incheon St. Mary’s Hospital, Incheon, Korea (the Republic of);
2Radiation Oncology, Seoul St. Mary’s Hospital, Seoul, Korea (the Republic of)
Objective: Desmoid tumors are rare non-malignant tumors and account for less than 3 percent of all soft tissue tumors. The disease, also known as aggressive fibromatosis, do not metastasize or dedifferentiate, but are locally aggressive tumors that can recur. The optimal treatment of the disease is not yet established. The aim of this study was to examine the outcome of radiotherapy in desmoid tumors and identify the therapeutic value of radiotherapy in the treatment of desmoid tumors.
Methods: Patients diagnosed with desmoid tumors and treated with radiotherapy between January, 2000 and December, 2018 were included. Twenty-two patients’ data were retrospectively analyzed. Two patients had Gardner’s syndrome. Fourteen patients (63.6%) were treated with radiotherapy after recurrence and eight (36.4%) patients were treated at first diagnosis. Seventeen patients (77.3%) were treated postoperatively, while five patients (22.7%) were treated radically. Radiotherapy target was created with 1.5 – 3 cm added to gross tumor or operative tumor bed. Median radiotherapy dose was 55.8 Gy, delivered with 1.8 – 2.3 Gy per fraction.
Results: Median follow up time was 35.1 months (range, 1.5 – 234.8 months). Twenty-one patients were assessed for recurrence since one patient was loss to follow up. Among them, four patients (18.2%) recurred after radiotherapy. Three local failures were classified as in-field failure while one was marginal failure. None of the failures occurred totally out-of-field. Time to local recurrence after radiotherapy ranged from 2.5 – 180.4 months. Except for the patient with 2.5 months follow up, others were treated with additional excision. One patient who recurred again after re-excision had underlying Gardner’s syndrome. In postoperative cases, patients treated with more than 55.8 Gy and with clear resection margin had better recurrence free survival, although the difference did not reach statistical significance.
Conclusion: Role of radiation therapy in desmoid tumors is of value since local control rate was satisfactory. Resection margin status and postoperative radiotherapy dose might be crucial when considering radiotherapy in the treatment of desmoid tumors.